Circuit-specific cell types in aging and Alzheimer's disease
衰老和阿尔茨海默病中的电路特异性细胞类型
基本信息
- 批准号:10625916
- 负责人:
- 金额:$ 284.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdrenergic AgentsAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnatomyAnimalsAreaAtlasesAxonBRAIN initiativeBehavioralBiochemicalBrainBrain regionCell CountCell NucleusCell SeparationCellsCensusesCerebellumCognitionCouplingDataData SetDeteriorationDiseaseDisease ProgressionDown-RegulationElectrophysiology (science)FemaleGene ProteinsGenetic DiseasesGoalsHippocampusHumanImpaired cognitionIndividualJointsKnock-inKnowledgeLabelLate Onset Alzheimer DiseaseLearningLinkLocationMapsMemoryMolecularMorphologyMusMutationNeurofibrillary TanglesNeuronsNuclear EnvelopeOutputPhysiologicalPrefrontal CortexPropertyRecombinant adeno-associated virus (rAAV)ResolutionSenile PlaquesSignal TransductionSourceStagingSystemTREM2 geneTestingage effectcell typeconnectomeentorhinal cortexepigenetic profilingepigenomicsgenetic varianthealthy aginginsightlocus ceruleus structuremalemulti-scale modelingmultiple omicsneuralneuropathologynovelpromoterresponsescreeningtranscriptometranscriptome sequencingtranscriptomics
项目摘要
Abstract
The long-term goal of this project is to define and identify circuit-specific cell types–cellular scale connectome–
that are selectively vulnerable to loss of cell bodies or axonal connections or change of transcriptomic
signatures of individual neurons during the progression of healthy aging and Alzheimer's disease (AD).
Evidence suggests that knowledge on the change of cellular scale connectomes–cell type-specific circuits by
coupling single cell transcriptome with brain connectivity– is needed for holistic understanding of aging and AD
and provides an experimentally tractable basis to address longitudinal changes. These aging- and AD-
associated changes may include loss of cell types, connectivity or alterations in transcriptomic signatures. This
approach employed here is to test the hypothesis that there are aging- or AD state-specific neural and
molecular circuits that drive the progression of aging and AD. A large body of evidence demonstrates that AD is
a heterogeneous, multifactorial disease that selectively affects certain brain regions, e.g. the entorhinal cortex
(EC), while other areas, such as the cerebellum, remain unaffected. Recent studies on the staging of AD
neuropathology showed AD-related neuropathology begins in the locus coeruleus (LC) or the EC, followed by
the hippocampus (HC) and then the prefrontal cortex (PFC). The LC contains both adrenergic (NA) and non-
noradrenergic neurons and provides the major NA inputs throughout the entire brain. Neuropathological
staging has shown that tangles fist appear in the LC and NA activation has been shown to ameliorate AD
deficits. The EC provides key cortical inputs to the HC, which is essential in learning memory. The PFC
provides the top-down regulation on various higher order functions. But cell types-based input and/or output
networks that are selectively vulnerable at the single neurons level are not well understood. As aging is a major
risk factor for AD, it is important to understand whether there are distinct, similar or overlapping selectively
vulnerable circuit-specific cell types between aging and AD. This project is to combine retrograde labeling with
multiomic sn-RNAseq and sn-ATACseq to link transcriptomic and epigenomic properties of cell types to
neuronal projections and investigate circuit-specific changes associated with progression of aging and AD in
four brain regions, namely the LC, EC, HC and PFC, in both male and female control and AD mice. For AD
mice, the APPNLF mouse line–that carries knockin human mutations in the amyloid precursor protein gene and,
importantly, expresses physiological levels of Aβ, mimicking late onset AD–will be used. The data from this
project will provide novel insights on the types of neurons vulnerable to degeneration and/or alterations of
molecular/signaling signature networks in a spatial and temporal fashion and the correlation with
neuropathology and cognitive impairment. This approach is a major step toward establishing multiscale models
that will help to fill the gap between the effects of genetic variants (e.g., APP, AOPE or TREM2) on brain
topology with molecular networks in aging and AD.
摘要
这个项目的长期目标是定义和识别特定于电路的细胞类型-细胞规模的连接体-
选择性地易受细胞体或轴突连接丢失或转录改变的影响
健康老化和阿尔茨海默病(AD)进展过程中单个神经元的特征。
有证据表明,关于细胞尺度连接体-细胞类型特定电路变化的知识通过
将单细胞转录组与脑连接相结合--是全面理解衰老和阿尔茨海默病的必要条件
并提供了解决纵向变化的实验上容易处理的基础。这些老化-和AD-
相关的变化可能包括细胞类型的丧失、连接性或转录特征的改变。这
这里采用的方法是检验这一假设,即存在衰老或AD状态特定的神经和
推动衰老和阿尔茨海默病进展的分子回路。大量证据表明,AD是
一种异质性、多因素的疾病,选择性地影响某些大脑区域,如内嗅皮层
(EC),而其他区域,如小脑,仍未受到影响。阿尔茨海默病分期研究进展
神经病理学显示,AD相关的神经病理始于蓝斑(LC)或EC,其次是
海马体(HC),然后是前额叶皮质(PFC)。LC既含有肾上腺素(NA),又含有非肾上腺素
去甲肾上腺素能神经元,并提供整个大脑的主要NA输入。神经病理学
分期表明,LC中出现了缠绕拳头,NA激活已被证明可以改善AD
赤字。EC向HC提供关键的皮质输入,而HC在学习记忆中是必不可少的。PFC
对各种高阶函数提供自上而下的调节。而是基于单元类型的输入和/或输出
在单个神经元水平上选择性地易受攻击的网络并没有得到很好的理解。因为老龄化是一个主要问题
AD的危险因素,了解选择性地存在明显、相似或重叠是很重要的
衰老和阿尔茨海默病之间易受攻击的电路特定细胞类型。该项目是结合逆行标记和
多组体sn-RNAseq和sn-ATACseq将细胞类型的转录和表观基因组特性连接到
神经元投射和研究与衰老和阿尔茨海默病进展相关的电路特异性变化
在雄性和雌性对照组和AD小鼠中,有四个脑区,即LC,EC,HC和PFC。对于AD
小鼠,APPNLF小鼠系--携带人类淀粉样前体蛋白基因的敲门突变,
重要的是,表达生理水平的Aβ,模拟迟发性AD-将被使用。来自这里的数据
该项目将为易受变性和/或改变影响的神经元类型提供新的见解
空间和时间方式的分子/信号签名网络以及与
神经病理学和认知障碍。这种方法是朝着建立多尺度模型迈出的重要一步
这将有助于填补遗传变异(如APP、AOPE或TREM2)对大脑的影响之间的空白
衰老和AD中分子网络的拓扑学。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
M MARGARITA BEHRENS其他文献
M MARGARITA BEHRENS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('M MARGARITA BEHRENS', 18)}}的其他基金
Circuit-specific cell types in aging and Alzheimer's disease
衰老和阿尔茨海默病中的电路特异性细胞类型
- 批准号:
10431698 - 财政年份:2022
- 资助金额:
$ 284.45万 - 项目类别:
Ultra-high Throughout Single Cell Multi-omic Analysis of Histone Modifications and Transcriptome in Mouse and Human Brains
小鼠和人脑组蛋白修饰和转录组的超高通量单细胞多组学分析
- 批准号:
10369242 - 财政年份:2021
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic cell-type classification and regulatory element identification in the human brain
人脑表观基因组细胞类型分类和调控元件鉴定
- 批准号:
10018649 - 财政年份:2019
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic cell-type classification and regulatory element identification in the human brain
人脑表观基因组细胞类型分类和调控元件鉴定
- 批准号:
10248439 - 财政年份:2019
- 资助金额:
$ 284.45万 - 项目类别:
The role of DNA methylation dynamics and patterning in postmitotic neuronal-maturation
DNA 甲基化动力学和模式在有丝分裂后神经元成熟中的作用
- 批准号:
9285686 - 财政年份:2017
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic Approaches for Unbiased Single Human-Neuron Subtype Census
无偏见的单个人类神经元亚型普查的表观基因组方法
- 批准号:
9357694 - 财政年份:2016
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic Approaches for Unbiased Single Human-Neuron Subtype Census
无偏见的单个人类神经元亚型普查的表观基因组方法
- 批准号:
9228115 - 财政年份:2016
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic mapping approaches for cell-type classification in the brain
用于大脑细胞类型分类的表观基因组图谱方法
- 批准号:
9107493 - 财政年份:2014
- 资助金额:
$ 284.45万 - 项目类别:
Epigenomic mapping approaches for cell-type classification in the brain
用于大脑细胞类型分类的表观基因组图谱方法
- 批准号:
8935938 - 财政年份:2014
- 资助金额:
$ 284.45万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 284.45万 - 项目类别:
Research Grant